The present invention pertains to combination radiotherapy of tumors and more specifically to pharmaceutical compositions and methods of treatment and therapy designed to sensitize tumors in animals, notably humans, and render them more sensitive to radiation, thus significantly reducing the amount of radiation required to kill neoplastic cells while at the same time making the radiation far more tissue specific to the tumor site.
More conventional radiation sensitizers are hypoxic cell sensitizers such as the antifilarial agent, misonidazole, which causes the complexities of neurotoxicity when it is utilized in humans. The 5-halogenated pyrimidine analogs are very distinct agents from the hypoxic cell sensitizers, for they have a completely different mode of action. We have found that cultured mammalian cells, when exposed to bromo-2'-deoxyuridine (BrdU) or other halogenated analogs of thymidine incorporate the compound into DNA resulting in sensitization of these cells to X-irradiation. Rapid catabolism or degradation of BrdU has limited its clinical effectiveness for the sensitization of rapidly growing neoplasias.
We have determined that 5-chloro-2'-deoxycytidine (CldC), which is not readily degraded due to the 4-amino group that protects the compound from catabolism by nucleoside phosphorylases, is anabolized by a different set of enzymes than the corresponding dU analog. In addition CldC is less cytotoxic than CldU. An object of the present invention is to define a class of stable, selective cell sensitizers that are not easily catabolized against tumors, both rapidly and moderately growing and malignant, and that will allow the X-ray therapist to focus the X-ray beam (or other source of radiation) on the tumor tissue site using significantly less, say one-fourth, of the dose of radiation otherwise required to achieve the same extent of tumor kill without damage to the underlying tissue. Expressed in another way, the radiotherapist is able to more aggressively kill neoplastic tissue while causing no more damage to normal tissue using the procedures and materials of the present invention than with conventional modalities of irradiation.
Thus an object of the present invention is to provide therapeutic materials and procedures for treating skin lesions using, for instance, ultraviolet light, near visible light (313 nm), and for solid tumors: X- or gamma ray, beta, neutron and other radiation entities.
Another object of the invention is to sensitize possible sites of metastic invasion to radiation, particularly X-ray, using the disclosed materials and procedures.
Should the patient develop toxcicity from the mildly aggressive therapy employed, particularly with the pretreatment with FdU and PALA either before or with the sensitizing composition, thymidine or deoxycytidine, two non-toxic metabolites, may be provided the patient at the conclusion of radiation therapy. These serve to mitigate the untoward effects, if any, of the drug therapy by antagonizing or reversing any toxic effects of the chemotherapeutic agents employed.
The method of the present invention may be used primarily with x-ray or gamma (derived from cobalt, for example) radiation. We also consider the procedure to be effective with the use of ultraviolet light, near visible light (313 nm) for skin lesions and for beta, neutron and other radiation entities. The molecular basis of sensitization has been clearly established for ultraviolet light (260 nm) and near visible light (313 nm) (both nonpenetrating) and for X- or gamma-radiation.